Glioblastoma multiforme (GBM), the most common and malignant of all gliomas, has a median survival time of 14.6 months. Standard of care chemotherapy using temozolomide (TMZ) is effective initially, but the GBM inevitably recurs, and these recurrent tumors are resistant to TMZ. There are currently no effective treatment options for patients with TMZ-resistant, recurrent tumors. Therefore identifying drugs that target TMZ-resistant tumors is critical. Recently a monoterpene, perillyl alcohol (POH), was shown to have moderate success for recurrent GBM, but only when used at high doses, which unfortunately results in toxicity. Our approach is to conjugate TMZ to POH to produce a novel agent, TMZ-POH, to target TMZ-resistant recurrent GBMs. Based on the hypothesis that these drugs together are more effective than either drug alone, in collaboration with our small business partner; we have successfully conjugated TMZ to POH. In preliminary data we demonstrate that this novel conjugate has as much as 10 times more cytotoxic against TMZ-resistant glioma cells, as compared to either agent alone or the mixture of the two at equimolar doses. Furthermore, the TMZ-POH conjugate is effective against a variety of TMZ-resistant GBM cells, and glioma stem cells (GSC), the chemo- and radiation resistant population responsible for initiating recurrent GBMs. In vivo data show that TMZ-POH is well tolerated, and is effective in intracranial tumors. The proposed aims will (1) identify the mechanism(s) of TMZ-POH activity on TMZ- resistant glioma cells and glioma cancer stem cells in vitro, and (2) determine effects of TMZ-POH at different doses, and modes of administration on intracranial glioma tumor growth in vivo in immune incompetent and immune competent animals, and measure the biodistribution of TMZ-POH in these different protocols. Completion of these aims will identify ways to optimize the potency of this agent to insure maximum efficacy. The present investigation will provide pre-clinical data to determine efficacy of TMZ-POH in reducing or eliminating TMZ-resistant brain tumors. The overall goal is to validate and establish TMZ-POH as a novel chemotherapeutic agent with outstanding activity against drug-resistant, recurrent GBM tumors.